Stroke outcomes among participants randomized to chlorthalidone, amlodipine or lisinopril in ALLHAT.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double-blind, practice-based, active-control, comparative effectiveness trial in 33,357 high-risk hypertensive participants. ALLHAT compared cardiovascular disease outcomes in participants initially treated with an angiotensin-converting enzyme inhibitor (lisinopril), a calcium channel blocker (amlodipine), or a thiazide-type diuretic (chlorthalidone). We report stroke outcomes in 1517 participants in-trial and 1596 additional participants during post-trial passive surveillance, for a total follow-up of 8-13 years. Stroke rates were higher with lisinopril (6-year rate/100 = 6.4) than with chlorthalidone (5.8) or amlodipine (5.5) in-trial but not including post-trial (10-year rates/100 = 13.2 [chlorthalidone], 13.1[amlodipine], and 13.7 [lisinopril]). In-trial differences were driven by race (race-by-lisinopril/chlorthalidone interaction P = .005, race-by-amlodipine/lisinopril interaction P = .012) and gender (gender-by-lisinopril/amlodipine interaction P = .041), separately. No treatment differences overall, or by race or gender, were detected over the 10-year period. No differences appeared among treatment groups in adjusted risk of all-cause mortality including post-trial for participants with nonfatal in-trial strokes. Among Blacks and women, lisinopril was less effective in preventing stroke in-trial than either chlorthalidone or amlodipine, even after adjusting for differences in systolic blood pressure. These differences abated by the end of the post-trial period.

Characteristics and long-term follow-up of participants with peripheral arterial disease during ALLHAT.

BACKGROUND: Hypertension is a major risk factor for peripheral artery disease (PAD). Little is known about relative efficacy of antihypertensive treatments for preventing PAD. OBJECTIVES: To compare, by randomized treatment groups, hospitalized or revascularized PAD rates and subsequent morbidity and mortality among participants in the Antihypertensive and Lipid-Lower Treatment to Prevent Heart Attack Trial (ALLHAT). DESIGN: Randomized, double-blind, active-control trial in high-risk hypertensive participants. PARTICIPANTS: Eight hundred thirty participants with specified secondary outcome of lower extremity PAD events during the randomized phase of ALLHAT. INTERVENTIONS/EVENTS: In-trial PAD events were reported during ALLHAT (1994-2002). Post-trial mortality data through 2006 were obtained from administrative databases. Mean follow-up was 8.8 years. MAIN MEASURES: Baseline characteristics and intermediate outcomes in three treatment groups, using the Kaplan-Meier method to calculate cumulative event rates and post-PAD mortality rates, Cox proportional hazards regression model for hazard ratios and 95 % confidence intervals, and multivariate Cox regression models to examine risk differences among treatment groups. KEY RESULTS: Following adjustment for baseline characteristics, neither participants assigned to the calcium-channel antagonist amlodipine nor to the ACE-inhibitor lisinopril showed a difference in risk of clinically advanced PAD compared with those in the chlorthalidone arm (HR, 0.86; 95 % CI, 0.72-1.03 and HR, 0.98; 95 % CI, 0.83-1.17, respectively). Of the 830 participants with in-trial PAD events, 63 % died compared to 34 % of those without PAD; there were no significant treatment group differences for subsequent nonfatal myocardial infarction, coronary revascularizations, strokes, heart failure, or mortality. CONCLUSIONS: Neither amlodipine nor lisinopril showed superiority over chlorthalidone in reducing clinically advanced PAD risk. These findings reinforce the compelling need for comparative outcome trials examining treatment of PAD in high-risk hypertensive patients. Once PAD develops, cardiovascular event and mortality risk is high, regardless of type of antihypertensive treatment.

Are there any new pharmacologic therapies on the horizon to better treat hypertension? A state-of-the-art paper.

Hypertension is the most important cardiovascular risk factor. We have witnessed a significant improvement in hypertension treatment and control and an impressive growth in the pharmacologic options available to clinicians and hypertension specialists. With up to a third of patients with hypertension not at the recommended goal blood pressures, it is critically important to develop novel therapeutic approaches to better treat hypertension. This review will explore the ever-expanding horizon of antihypertensive treatment and will focus on 2 major areas of drug development. First, we will review novel targets for pharmacologic treatment and novel molecules and classes of drugs in various phases of development and recognize the limitations we face in their transition from research and development to clinical practice. Then, we will discuss an expanding array of combination strategies to better treat hypertension with the goal of minimizing the burden of cardiovascular and renal complications of hypertension.

Mortality and morbidity during and after Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: results by sex.

To determine whether an angiotensin-converting enzyme inhibitor (lisinopril) or calcium channel blocker (amlodipine) is superior to a diuretic (chlorthalidone) in reducing cardiovascular disease incidence in sex subgroups, we carried out a prespecified subgroup analysis of 15 638 women and 17 719 men in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Total follow-up (active treatment + passive surveillance using national administrative databases to ascertain deaths and hospitalizations) was 8 to 13 years. The primary outcome was fatal coronary heart disease or nonfatal myocardial infarction. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (coronary heart disease death, nonfatal myocardial infarction, stroke, angina, coronary revascularization, heart failure [HF], or peripheral vascular disease), and end-stage renal disease. In-trial rates of HF, stroke, and combined cardiovascular disease were significantly higher for lisinopril compared with chlorthalidone, and rates of HF were significantly higher for amlodipine compared with chlorthalidone in both men and women. There were no significant treatment sex interactions. These findings did not persist through the extension period with the exception of the HF result for amlodipine versus chlorthalidone, which did not differ significantly by sex. For both women and men, rates were not lower in the amlodipine or lisinopril groups than in the chlorthalidone group for either the primary coronary heart disease outcome or any other cardiovascular disease outcome, and chlorthalidone-based treatment resulted in the lowest risk of HF. Neither lisinopril nor amlodipine is superior to chlorthalidone for initial treatment of hypertension in either women or men. Clinical Trial Registration- clinicaltrials.gov; Identifier: NCT00000542.

Impact of alpha 1-adrenergic antagonist use for benign prostatic hypertrophy on outcomes in patients with heart failure.

Previous clinical trials have shown that alpha(1)-adrenergic antagonists are not effective in subjects with heart failure (HF) and might increase HF rates when used for hypertension. However, alpha(1)-adrenergic antagonists may be prescribed to subjects with HF who have symptomatic benign prostatic hyperplasia. We sought to determine any association between alpha(1)-adrenergic antagonist use, commonly prescribed for benign prostatic hyperplasia, and the clinical outcomes of subjects with HF receiving contemporary therapy. An existing database of 388 subjects with decompensated HF admissions from 2002 to 2004 at the Veterans Affairs Hospital was analyzed according to the use of alpha(1)-adrenergic antagonists at discharge. Covariate-adjusted Cox proportional hazard models were used to examine any association with future admissions for decompensated HF and total mortality. Alpha-1-adrenergic antagonist therapy was prescribed in 25% of our HF population, predominantly for benign prostatic hyperplasia, and was not associated with significant increases in the combined risk of all-cause mortality and rehospitalization for HF (hazard ratio 1.24, 95% confidence interval 0.93 to 1.65, p = 0.14), HF hospitalization (hazard ratio 1.20, 95% confidence interval 0.85 to 1.70, p = 0.31), or all-cause mortality (hazard ratio 1.10, 95% confidence interval 0.78 to 1.56, p = 0.57). In patients not receiving beta-blocker therapy, alpha(1)-adrenergic antagonist therapy was significantly associated with increased HF hospitalizations (hazard ratio 1.94, 95% confidence interval 1.14 to 3.32, p = 0.015). In conclusion, in patients with chronic HF, the use of alpha(1)-adrenergic antagonists was significantly associated with more HF hospitalizations when prescribed without concomitant beta blockade. Thus, background beta-blocker therapy appears to be protective against the potential harmful effects of alpha(1)-adrenergic antagonist therapy in patients with HF.

Digoxin and clinical outcomes in systolic heart failure patients on contemporary background heart failure therapy.

Previous trials have shown that digoxin was beneficial in patients with heart failure (HF). However, these studies were conducted before the incorporation of beta blockers as standard therapy for patients with HF. The purpose of this study was to determine the effect of digoxin in patients with HF on a contemporary regimen of renin-angiotensin inhibition and beta blockade. In 347 almost exclusively men, data pertaining to the index hospitalization and occurrence of all-cause mortality or readmission for HF were collected. Cox proportional hazard modeling was used. Patients on digoxin therapy had a lower left ventricular (LV) ejection fraction (EF), higher prevalence of previous hospitalizations for HF and atrial fibrillation, and lower prevalence of hypertension. After adjustment for age, LVEF, history of HF hospitalizations, New York Heart Association class, presence of chronic renal insufficiency, presence of atrial fibrillation, and prescriptions for beta blockers and angiotensin converting enzyme inhibitors or angiotensin receptor blockers, HF hospitalizations (hazard ratio 1.08, 95% confidence interval [CI] 0.77 to 1.50, p = 0.66), total mortality (hazard ratio 1.03, 95% CI 0.78 to 1.35, p = 0.85), or the combined end point of HF hospitalization and total mortality (hazard ratio 1.11, 95% CI 0.81 to 1.53, p = 0.52) were not different in patients using digoxin compared with those not using digoxin. Clinical outcomes were not different in subgroups of patients with EF < or =25%, New York Heart Association class III or IV, atrial fibrillation, heart rate < or =60 beats/min, or patients on beta-blocker therapy. In conclusion, digoxin use was not associated with a decrease in HF hospitalizations or overall mortality rates in a cohort of hospitalized patients with HF with LV systolic dysfunction on contemporary background HF treatment including angiotensin-converting enzyme inhibitors and beta blockers.

Herpes zoster and its cardiovascular complications in the elderly--another look at a dormant virus.

Herpes zoster (shingles) is a reactivation of latent Varicella-zoster virus (VZV). We present a case of pleuropericarditis simulating acute myocardial infarction and another with complete heart block in the setting of acute/recent VZV reactivation. These cases are consistent with a modified concept: (1) the VZV dormancy is comprised of multiple foci of infections in the sensory and autonomic ganglia, and (2) the VZV reactivation could involve co-incident activations of two or more loci. Recognition of this possibility of cardiovascular complications of VZV should be helpful in the clinical management of the elderly, in the differential diagnosis of chest pain, ST elevation, and heart block etiology in the setting of acute or recent VZV reactivation.

Prevention of vascular events in patients with cerebrovascular disease: efficacy and appropriate duration of antiplatelet therapy.

Antiplatelet therapy has shown consistent benefit in the prevention of secondary stroke. The paucity of head-to-head studies of different antiplatelet regimens, assessment of comparative efficacy, and optimal treatment duration requires evaluation and comparison of clinical studies that vary extensively in design and follow-up. Evidence for aspirin benefit in secondary stroke prevention is strong, but existing studies provide little guidance with regard to treatment duration. The efficacy of clopidogrel in secondary event prevention is significantly greater than that of aspirin for patients with a history of peripheral artery disease, but does not differ from that of aspirin for patients with a history of stroke or myocardial infarction. Relative to clopidogrel alone, the addition of aspirin to clopidogrel results in increased risk for life-threatening bleeding episodes similar in absolute magnitude to the reduction of secondary event risk in patients with stroke. Benefits associated with clopidogrel occur early in the course of therapy; few data support clopidogrel use for longer than 1 year after stroke. Monotherapy with extended-release dipyridamole (ER-DP) provides reduction in secondary stroke risk similar to aspirin; however, the combination of aspirin plus ER-DP significantly reduces risk relative to either agent alone. Compared with placebo and monotherapy with either agent, risk reduction for the aspirin plus ER-DP combination continued through 24 months, with no concomitant increase in bleeding risk. Additional clinical studies should provide needed comparisons of efficacy and guidance with regard to optimal duration of therapy.

Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril.

CONTEXT: Few cardiovascular outcome data are available for blacks with hypertension treated with angiotensin-converting enzyme (ACE) inhibitors or calcium channel blockers (CCBs). OBJECTIVE: To determine whether an ACE inhibitor or CCB is superior to a thiazide-type diuretic in reducing cardiovascular disease (CVD) incidence in racial subgroups. DESIGN, SETTING, AND PARTICIPANTS: Prespecified subgroup analysis of ALLHAT, a randomized, double-blind, active-controlled, clinical outcome trial conducted between February 1994 and March 2002 in 33,357 hypertensive US and Canadian patients aged 55 years or older (35% black) with at least 1 other cardiovascular risk factor. INTERVENTIONS: Antihypertensive regimens initiated with a CCB (amlodipine) or an ACE inhibitor (lisinopril) vs a thiazide-type diuretic (chlorthalidone). Other medications were added to achieve goal blood pressures (BPs) less than 140/90 mm Hg. MAIN OUTCOME MEASURES: The primary outcome was combined fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI), analyzed by intention-to-treat. Secondary outcomes included all-cause mortality, stroke, combined CVD (CHD death, nonfatal MI, stroke, angina, coronary revascularization, heart failure [HF], or peripheral vascular disease), and end-stage renal disease. RESULTS: No significant difference was found between treatment groups for the primary CHD outcome in either racial subgroup. For amlodipine vs chlorthalidone only, HF was the only prespecified clinical outcome that differed significantly (overall: relative risk [RR], 1.37; 95% confidence interval [CI], 1.24-1.51; blacks: RR, 1.46; 95% CI, 1.24-1.73; nonblacks: RR, 1.32; 95% CI, 1.17-1.49; P<.001 for each comparison) with no difference in treatment effects by race (P = .38 for interaction). For lisinopril vs chlorthalidone, results differed by race for systolic BP (greater decrease in blacks with chlorthalidone), stroke, and combined CVD outcomes (P<.001, P = .01, and P = .04, respectively, for interactions). In blacks and nonblacks, respectively, the RRs for stroke were 1.40 (95% CI, 1.17-1.68) and 1.00 (95% CI, 0.85-1.17) and for combined CVD were 1.19 (95% CI, 1.09-1.30) and 1.06 (95% CI, 1.00-1.13). For HF, the RRs were 1.30 (95% CI, 1.10-1.54) and 1.13 (95% CI, 1.00-1.28), with no significant interaction by race. Time-dependent BP adjustment did not significantly alter differences in outcome for lisinopril vs chlorthalidone in blacks. CONCLUSIONS: In blacks and nonblack subgroups, rates were not lower in the amlodipine or lisinopril groups than in the chlorthalidone group for either the primary CHD or any other prespecified clinical outcome, and diuretic-based treatment resulted in the lowest risk of heart failure. While the improved outcomes with chlorthalidone were more pronounced for some outcomes in blacks than in nonblacks, thiazide-type diuretics remain the drugs of choice for initial therapy of hypertension in both black and nonblack hypertensive patients.

Cardiovascular outcomes using doxazosin vs. chlorthalidone for the treatment of hypertension in older adults with and without glucose disorders: a report from the ALLHAT study.

Insulin resistance underlies most glucose disorders in adults and is associated with an increased risk of cardiovascular disease. Alpha blockers decrease insulin resistance, whereas diuretics increase insulin resistance. The authors studied the effects of these two classes of hypertension medications (doxazosin, an a blocker, and chlorthalidone, a diuretic) on cardiovascular disease outcomes in adults aged >55 years with hypertension and glucose disorders who were participants in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (8749 had known diabetes mellitus and 1690 had a newly diagnosed glucose disorder [fasting glucose >/=110 mg/dL]). There was no difference in either group between the chlorthalidone- and doxazosin-based treatments with regard to fatal or nonfatal myocardial infarction or all-cause mortality. There was, however, a difference for combined cardiovascular disease (myocardial infarction, revascularization procedures, angina, stroke, heart failure, and peripheral arterial disease) in favor of the diuretic. This difference was due primarily to an increased heart failure risk in those treated with doxazosin (relative risk, 1.85; 95% confidence interval, 1.56-2.19) in the known diabetes mellitus group and a relative risk of 1.63 (95% confidence interval, 1.05-2.55) in those with a newly diagnosed glucose disorder despite lower glucose levels on follow-up in those treated with a blockers. The authors conclude that treatment of hypertension with doxazosin in adults with glucose disorders incurs the same risk of coronary heart disease as treatment with chlorthalidone; however, treatment with doxazosin increases the risk of combined cardiovascular disease and heart failure despite lower glucose levels.

Characteristics and lipid distribution of a large, high-risk, hypertensive population: the lipid-lowering component of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) consisted of 42,418 participants randomized to one of four antihypertensive treatment groups: chlorthalidone, amlodipine, lisinopril, or doxazosin. A subset of these participants with fasting low-density lipoprotein cholesterol levels 100-189 mg/dL were randomized into a lipid-lowering component: 5170 to receive pravastatin (40 mg daily) and 5185 to receive usual care. This report describes the characteristics and lipid distribution of these participants. There were no important differences between the randomized treatment groups. Women had higher total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol than men. There was a similar finding for black participants compared with whites, except blacks had lower triglycerides. Diabetics had lower high-density lipoprotein cholesterol and higher triglycerides than nondiabetics, and patients with body mass index <25 kg/m(2) had higher high-density lipoprotein cholesterol but lower low-density lipoprotein cholesterol and triglycerides than patients with higher body mass index. The success of the randomization of this large, diverse population and the differences in the lipid distributions among its subgroups will allow further understanding of optimal lipid-lowering treatment.